The synthesis and secretion of pulmonary surfactant, a complex mixture of lipids and proteins, by the alveolar epithelium is essential for maintaining the structural integrity of the alveolus during respiration; surfactant insufficiency leads to respiratory distress syndrome, a leading cause of morbidity and mortality i neonates. Surfactant- associated Protein B (SP-B), referred to as SPL (Phe) in the previous funding period, is absolutely required for the function of pulmonary surfactant. Human SP-B is synthesized as a preproprotein of 381 amino acids which is processed to the biologically active peptide of 79 residues by proteolytic cleavage of N- and C-terminal peptides from the precursor. Proteolytic processing of the proprotein, therefore, represents a critical steps in the overall regulation of SP-B expression. The current proposal describes studies to: (1) identify the protease(s) and cleavage sites involved in SP-B proprotein processing in vivo, (2) identify peptide domains involved in the transport and sorting of SP-B within the secretory pathway of the Type II cell, (3) define the role of SP-B in directing surfactant phospholipid trafficking in the biosynthetic and endocytic pathways of the Type II cell, and (4) determine the fate and function of the N- and C-terminal peptides following cleavage form the SP-B proprotein. The overall goal of this research is to determine how SP-B processing is integrated with the biosynthesis and metabolism of other components of the pulmonary surfactant system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036055-13
Application #
2609238
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1985-12-01
Project End
1998-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Beck, D C; Ikegami, M; Na, C L et al. (2000) The role of homodimers in surfactant protein B function in vivo. J Biol Chem 275:3365-70
Beck, D C; Na, C L; Whitsett, J A et al. (2000) Ablation of a critical surfactant protein B intramolecular disulfide bond in transgenic mice. J Biol Chem 275:3371-6
Lin, S; Na, C L; Akinbi, H T et al. (1999) Surfactant protein B (SP-B) -/- mice are rescued by restoration of SP-B expression in alveolar type II cells but not Clara cells. J Biol Chem 274:19168-74
Akinbi, H T; Bhatt, H; Hull, W M et al. (1999) Altered surfactant protein B levels in transgenic mice do not affect clearance of bacteria from the lungs. Pediatr Res 46:530-4
Akinbi, H T; Breslin, J S; Ikegami, M et al. (1997) Rescue of SP-B knockout mice with a truncated SP-B proprotein. Function of the C-terminal propeptide. J Biol Chem 272:9640-7
Yarus, S; Weaver, T E; Rosen, J M (1997) The carboxy-terminal domain of human surfactant protein B is not required for secretion in milk of transgenic mice. Front Biosci 2:a1-8
Clark, J C; Weaver, T E; Iwamoto, H S et al. (1997) Decreased lung compliance and air trapping in heterozygous SP-B-deficient mice. Am J Respir Cell Mol Biol 16:46-52
Yarus, S; Greenberg, N M; Wei, Y et al. (1997) Secretion of unprocessed human surfactant protein B in milk of transgenic mice. Transgenic Res 6:51-7
Lin, S; Akinbi, H T; Breslin, J S et al. (1996) Structural requirements for targeting of surfactant protein B (SP-B) to secretory granules in vitro and in vivo. J Biol Chem 271:19689-95
Holzinger, A; Phillips, K S; Weaver, T E (1996) Single-step purification/solubilization of recombinant proteins: application to surfactant protein B. Biotechniques 20:804-6, 808

Showing the most recent 10 out of 23 publications